Tributyltin hydride as a selective reducing agent for aryl enones

Article abstract of DOI:10.1055/s-0030-1261231

Aryl enones undergo selective 1,4-reduction to the corresponding saturated ketones with two equivalents of tributyltin hydride in the presence of a wide range of other potentially reducible functional groups, including alkyl enone. Additionally during this investigation reductive cyclization of bisenones to give five- and six-membered carbocycles via an ,-coupling process was observed. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1261231

LETTER
2355
Tributyltin Hydride as a Selective Reducing Agent for Aryl Enones
Tributyltin
H
ydride as
a
a
S
elective
r
R
educin
i
g
A
gen
e
t
for Aryl Enone
s
E. Krafft,* Dinesh V. Vidhani, John W. Cran
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA
Fax +1(850)6447409; E-mail: mek@chem.fsu.edu
Received 10 June 2011
O
O
O
O
Abstract: Aryl enones undergo selective 1,4-reduction to the corre-
sponding saturated ketones with two equivalents of tributyltin hy-
dride in the presence of a wide range of other potentially reducible
functional groups, including alkyl enone. Additionally during this
investigation reductive cyclization of bisenones to give five- and
six-membered carbocycles via an a,b-coupling process was ob-
served.
(2)
90%
6
6
2b
2a
Equation 2
Key words: chemoselectivity, selective 1,4-reduction, cyclization,
stannane, enone
Gratifyingly, when these conditions were applied to bis-
enone 2a, (Equation 2), the phenyl vinyl ketone was re-
duced selectively in good yield in the presence of the
methyl vinyl ketone.
During the course of our synthetic studies we required a
chemoselective method for the 1,4-reduction of aryl
enones, particularly in the presence of alkyl vinyl ketones.
While a large variety of methods are reported for the con-
jugate reduction of a,b-unsaturated carbonyl com-
pounds,1–8 none appeared to possess the degree of
selectivity we desired. However, in a study by the Noltes
group9 on the use of organotin hydride compounds as re-
ducing agents for unsaturated carbonyl compounds it was
shown that aryl enones underwent 1,4-reduction in the
presence of tributyltin hydride while methyl vinyl ketone
was inert. In contrast, other organotin hydrides examined
in the paper such as triphenyltin hydride reduced both
types of enones, however no direct ‘one-pot’ comparison
was made and no study was carried out to determine the
scope of the reaction. Herein we describe the expanded
scope and synthetic utility of this selective reduction in
addition to providing mechanistic insight.
A variety of functionalized aryl enones were subsequently
screened to test the utility and scope of the method
(Table 1). In general it was found that the reaction exhib-
ited excellent selectivity for aryl enones in the presence of
a wide range of substituents and functional groups. Both
aromatic and aliphatic groups were tolerated at the enone
b-carbon (entry 1 vs. entry 2). A variety of substituents on
the aryl ring were acceptable and no unwanted reduction
was seen (entries 3–5). However, it appeared from the ex-
tremely slow reduction in entry 5, that substituents at the
a-position inhibited the reduction, probably due to steric
constraints in the transition state (vida infra). Potentially
reducible substituents on other positions on the molecule
were also found to be compatible with the method (entries
6–8). Aryl enones were also reduced selectively and in
high yields in the presence of an a,b-unsaturated alde-
hyde, ketone or ester (entries 9–12).
An initial investigation into the reduction of phenyl 1-pro-
penyl ketone (1a; Equation 1) with tributyltin hydride re-
vealed two equivalents of the stannane in refluxing
benzene at 0.3 M concentration to be the optimum condi-
tions, in which case the reaction was complete in three
hours. With one equivalent, the reaction failed to go to
completion and a mixture of starting material and reduced
product was obtained, while additional equivalents of tin
hydride beyond two were not beneficial to the reaction
rate or efficiency.
Table 1 Reaction Scopea
Entry Enone
Product
Isolated
yield (%)
O
O
Ph
Ph
1
2
98
94
1a
1b
O
O
O
O
Ph
Ph
Bu3SnH (2 equiv)
(1)
Ph
Ph
Ph
Ph
PhH, 80 °C, 3 h
98%
2a
2b
1a
1b
O
O
Equation 1
3
92
MeO
MeO
SYNLETT 2011, No. 16, pp 2355–2358
x
x
.x
x
.2
0
1
1
Advanced online publication: 13.09.2011
DOI: 10.1055/s-0030-1261231; Art ID: S05311ST
3a
3b
© Georg Thieme Verlag Stuttgart · New York

2356
M. E. Krafft et al.
LETTER
Table 1 Reaction Scopea (continued)
followed by quenching of the resultant tin enolate with
water. We found that reactions conducted in the presence
of D2O resulted in deuterium incorporation at the a-posi-
tion. The possibility of a radical reaction pathway was
ruled out when the presence of the radical inhibitor, galvin-
oxyl, was found to have no detrimental effect on the out-
come of the reaction. Given the sluggishness of the
reaction in the case where an a-substituent was present on
the enone (Table 1, entry 5), we suspected that the initial
hydrostannylation proceeded through a cyclic transition
state A (Scheme 1), as the adoption of such a conforma-
tion would result in steric crowding between the a-substit-
uent and an aromatic ortho proton, as in C (Scheme 1).
Entry Enone
Product
Isolated
yield (%)
O
O
4
85
NC
NC
4a
4b
O
O
5
60b
95
97
72
Cl
5a
O
Cl
5b
O
Bu
O
O
Ph
Bu3SnH
Ph
Ph
6
7
8
Sn Bu
Bu
H
Ph
H3C
O
6a
6b
A
O
O
O
O
O
O
OSnBu3
Bu
O
Ph
H2O
Ar
H3C
Ph
Sn Bu
Bu
H
Ph
Ph
H
7a
7b
B
C
O
Br
O
Br
O
Ph
Ph
Scheme 1
8a
8b
Reduction via transition state A was supported by the ob-
servation that cyclic enone 13, which cannot adopt a
cyclic transition state owing to the conformational con-
straints imposed by the seven-membered ring, was inert to
reduction (Equation 3).
O
Ph
H
Ph
H
9
10
11
12
92
90
85
91
6
6
9a
9b
O
O
O
O
O
O
O
O
O
O
O
Bu3SnH (2 equiv), PhH
Ph
Ph
no reaction
(3)
reflux, 12 h
6
6
2
6
13
10b
10a
O
Equation 3
Ph
OEt
Ph
OEt
Interestingly, it was found that in the presence of tributyl-
tin hydride certain bisenones, (Table 2), underwent a re-
ductive cyclization via a net a,b-coupling of the
unsaturated systems to give five- and six-membered satu-
rated carbocycles. Related processes involving the cy-
clization of electron-deficient alkenes have been reported
by the Montgomery10 and Enholm11 groups, although in
their cases cyclization results from coupling at the b-posi-
tions. Presumably, in our case Michael addition of the tin
enolate onto the second unsaturated system occurs in pref-
erence to further reduction of the second phenyl vinyl ke-
tone functionality by stannane (entries 1 and 3, Table 2;
Scheme 2). Bisphenyl enone 15a (entry 1, Table 2), gave
the cyclized product in 95% yield while bisenone 16a (en-
try 2) gave 70% of the monocycle along with 30% of the
reduced product 16c (Figure 1) as an inseparable mixture.
2
11a
11b
O
Ph
OMe
Ph
OMe
6
12b
12a
a Reaction conditions: n-Bu3SnH (2 equiv), benzene (0.3 M), 80 °C,
3 h, resealable tube.
b Yield estimated from 1H NMR spectrum, reaction incomplete after
18 h.
Investigations were also carried out to determine the
mechanism of the reaction. The Noltes group9 reported
that the reaction proceeds via initial hydrostannylation
Synlett 2011, No. 16, 2355–2358 © Thieme Stuttgart · New York

LETTER
Tributyltin Hydride as a Selective Reducing Agent for Aryl Enones
2357
R
O
O
Ph
O
O
O
O
Ph
Ph
Ph
R
O
O
n-Bu3SnH
n
2
+
16c
17c
Ph
PhH, 80 °C
R
O
n-Bu3SnO
Ph
Figure 1
n
amount of tributyltin hydride to four equivalents resulted
in a slightly higher proportion of the reduced product.
With phenyl enone 18a (entry 4), it was possible to isolate
the cyclized product exclusively as the trans diastereomer
in 66% yield. Employing more dilute conditions resulted
in a cleaner reaction and improved yield in the case of
17a, although the product selectivity was not affected. In
the reaction of 18a no beneficial effect was observed how-
ever.
n
O
O
R
O
OSnn-Bu3
R
H2O
Ph
Ph
14
n
n
Scheme 2
In conclusion, we have found that under ionic conditions
Bu3SnH can act as a selective reducing agent for aryl
enones in the presence of a wide range of other functional
groups.12,13 Furthermore, a mode of reactivity has been
uncovered whereby bisenones can undergo reductive cy-
clization to give the five- and six-membered saturated car-
bocycles.
In the case of six-membered ring formation (entries 3 and
4, Table 2), the reactions were messier leading to lower
yields. Bisenone 17a (entry 3) gave the trans-disubstitut-
ed cyclized product along with the fully reduced product,
17c (Figure 1), as an inseparable mixture. Increasing the
Table 2 Reductive Cyclization of Bisenones in the Presence of Tributyltin Hydride
Entrya
Substrate
Product
Yield (%)
Yield (%)
Cyclized product
Reduced product
O
Ph
O
O
O
95b
0
Ph
1
Ph
Ph
15a
15b
O
O
O
O
2
3
70c,d
30c (16c)
Ph
Ph
16a
16b
O
O
n-Bu3SnH (2 equiv)
n-Bu3SnH (4 equiv)
n-Bu3SnH (2 equiv)
(0.1 M in benzene)
54c,e
43c,e
62c,e
13c (17c)
22c (17c)
16c (17c)
O
Ph
O
Ph
Ph
Ph
17a
17b
O
O
O
O
66e
58e
0
0
4
(0.1 M in benzene)
Ph
Ph
18a
18b
a Reaction conditions: n-Bu3SnH (2 equiv), benzene (0.3 M), 80 °C, 3 h, resealable tube.
b Only the cis isomer was detected by 1H NMR.
c Yields estimated from 1H NMR spectra. Inseparable mixture of products.
d A mixture of cis and trans was observed.
e Only the trans isomer detected by 1H NMR.
Synlett 2011, No. 16, 2355–2358 © Thieme Stuttgart · New York

2358
M. E. Krafft et al.
LETTER
concentrated en vacuo and purified by flash column
Acknowledgment
chromatography to give the reduced product as a clear oil.
(13) NMR data: 1b,14 3b,2 4b,15 5b,16 6b,17 7b,18 8b,19 9b,20 11b,21
15b,22 17b and 18b,23 17c.24 Compound 2b: 1H NMR (300
MHz, CD2Cl2): d = 7.95 (m, 2 H), 7.55 (m, 1 H), 7.47 (m, 2
H), 6.78 (dt, J = 15.95, 6.9 Hz, 1 H), 6.09 (dd, J = 16.0, 1.4
Hz, 1 H), 2.96 (t, J = 7.2 Hz, 2 H), 2.20 (s, 3 H), 2.09 (tdd,
J = 7.0, 7.0, 1.5 Hz, 2 H), 1.71 (tt, J = 7.15, 7.15 Hz, 2 H),
1.29–1.53 (m, 10 H). 13C NMR (75 MHz, CD2Cl2): d =
200.5, 198.6, 148.8, 137.7, 133.2, 131.7, 129.0, 128.4, 38.9,
32.9, 29.9, 29.7, 29.6, 28.6, 27.0, 24.7. Compound 10b: 1H
NMR (300 MHz, CD2Cl2): d = 9.48 (d, J = 8.0 Hz, 1 H), 7.95
(m, 2 H), 7.55 (m, 1 H), 7.47 (m, 2 H), 6.85 (dt, J = 15.7, 6.6
Hz, 1 H), 6.09 (dd, J = 15.2, 7.7 Hz, 1 H), 2.96 (t, J = 7.2 Hz,
2 H), 2.32 (dt, J = 7.4, 7.2 Hz, 2 H), 1.71 (tt, J = 7.2, 6.9 Hz,
2 H), 1.50 (tt, J = 6.9, 6.9 Hz, 2 H) 1.35 (m, 8 H). 13C NMR
(75 MHz, CD2Cl2): d = 200.2, 194.1, 159.17, 137.4, 133.1,
132.9, 128.7, 1281, 38.7, 32.8, 29.6, 29.5, 29.4, 29.3, 28.0,
24.4. Compound 12b: 1H NMR (300 MHz, CD2Cl2): d =
7.93 (m, 2 H), 7.55 (m, 1 H), 7.46 (m, 2 H), 6.94 (dt, J = 15.7,
6.9 Hz, 1 H), 5.80 (dd, J = 15.4, 1.4 Hz, 1 H), 3.67 (s, 3 H),
2.94 (t, J = 7.4 Hz, 2 H), 2.19 (tdd, J = 7.9, 6.9, 1.1 Hz, 2 H),
1.71 (tt, J = 7.2, 6.8 Hz, 2 H), 1.24–1.52 (m, 10 H). 13C NMR
(75 MHz, CD2Cl2): d = 200.3, 167.1, 149.8, 137.9, 132.9,
128.7, 128.1, 120.9, 51.4, 38.7, 32.3, 29.6, 29.5, 29.4, 29.2,
28.2, 24.4.
Support of this research from the MDS Research Foundation and
the NSF is gratefully appreciated.
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Typical Procedure for the Selective Reduction of Aryl
Enones: To a stirred solution of the aryl vinyl ketone (1.0
mmol) in benzene (3.3 mL, 0.3 M) in a resealable tube at r.t.
under argon was added tributyltin hydride (0.58 g, 2.0
mmol). The reaction mixture was subsequently heated to
80 °C for 3 h. Upon completion the reaction mixture was
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